ABSTRACT Zika virus (ZIKV) has spread rapidly throughout South and Central America since it was first reported in Brazil in early 2015. A temporally-related increase in the incidence of microcephaly a few months after the peak of the epidemic in Brazil prompted the World Health Organization to declare a ZIKV public health emergency of international concern. To slow the spread of ZIKV and prevent its severe consequences, a better understanding of modes of transmission is urgently needed. ZIKV, like many arboviruses, is transmitted by mosquitos, but several case reports suggest that it can be sexually transmitted, which is particularly concerning during pregnancy given the virus?s potential teratogenicity. The investigators propose to characterize the epidemiology of Zika virus as it emerges in a ZIKV-nave population in Len, Nicaragua via a cohort study of patients presenting to the city?s public hospital?s emergency department with fever, rash, and/or conjunctivitis. All participants will be interviewed with a questionnaire to determine risk factors for vector-borne and sexual acquisition of ZIKV. Each participant will provide blood, urine, and saliva to be screened for ZIKV, and those diagnosed with acute ZIKV will be followed for 6-12 months, providing serial biological specimens (blood, urine, saliva, semen, cervicovaginal fluid, and breast milk as applicable) to assess duration of shedding in various body compartments and assess potential for sexual transmission of ZIKV. Genital tract samples containing detectable virus will be used to inoculate cell cultures to evaluate viability of ZIKV in semen, cervicovaginal fluid, and breast milk. Next generation sequencing will be employed to determine if ZIKV isolates in the genital tract are replicating independently or contain quasispecies not found in the blood. NGS technology will also be applied to samples from household members including sexual partners of index cases to evaluate phylogenetic relationships between ZIKV strains transmitted by mosquito compared to those possibly transmitted through sexual contact. The University of North Carolina (UNC) and the University of Nicaragua (UNAN-Len) have a longstanding and productive research collaboration and are ideally poised to study the emerging ZIKV epidemic. Nicaragua is an ideal site to execute this study because of the high incidence of arboviral infections, the robust research infrastructure at the proposed site, and the strong collaboration between UNC and UNAN- Len. This unique collaboration affords us the ability to exchange research and analytic tools to better understand the epidemiology and pathogenesis of ZIKV as it emerges in a nave population in Nicaragua. This research will generate novel data that are fundamental to the advancement of prevention and control interventions, particularly interventions that go beyond typical vector control programs to prevent sexual transmission and avert potentially catastrophic congenital infection. The study will add to existing research infrastructure to develop capacity for future studies on ZIKV transmission with the ultimate goal of reducing the burden of disease and preventing the adverse outcomes associated with the infection.